Noninvasive brain imaging is used to study biological correlates of drug abuse in human volunteers. Positron emission tomography (PET) and electroencephalography (EEG) show that euphoriants reduce global and regional cerebral metabolic rates for glucose (CMRglc, rCMRglc), and increase a power. Changes in rCMRglc induced by morphine or cocaine and in EEG a power produced by morphine are correlated with positive affect. Cocaine-induced changes in rCMRglc but not in b power are related to mood. Buprenorphine, a mixed opioid agonist/antagonist, decreases regional CMRglc (rCMRglc), as do other abused drugs, such as morphine, cocaine, and nicotine. In subjects with histories of cocaine abuse, ongoing studies suggest that cocaine-related stimuli produce drug craving, arousal (desynchronization of a activity), and increased rCMRglc in areas of the limbic system. Patients with acquired immunodeficiency syndrome (AIDS) show metabolic defects in the limbic system, consistent with an involvement of the hippocampus and related areas in cognitive deficits associated with AIDS dementia. Drug abusers that are seronegative for human immunodeficiency virus manifest lower rCMRglc in visual association cortex and higher rCMRglc in orbitofrontal cortex than non-drug abusing controls matched for age and socioeconomic status. To determine whether these differences predate or result from drug abuse, rCMRglc and regional cerebral blood flow are studied in twins discordant for drug abuse. Magnetic resonance imaging is used to study brain structure, as related to personality and cognition in substance abusers. Volumetric analyses reveal no evidence of ventriculomegaly in substance abusers who are otherwise healthy. Ongoing studies assess potential differences in structure of the orbitofrontal cortex, a brain region that shows a difference in rCMRglc in drug abusers as compared to controls. Studies in newborn sheep assessed the effects of cocaine on cerebral blood flow (CBF). A single dose of cocaine almost doubled CBF at 30 s while arterial blood pressure was increased; CBF returned to control within 5 min. In sheep that received cocaine repeatedly, CBF 30 s after the fifth dose was stimulated as after the first, and remained elevated for 1 h. Cerebral vasodilation, combined with hypertension, may contribute to cocaine-associated neonatal neurologic damage. An improved form of a model for calculation of (CMRglc) from PET data has been developed to obviate the need for arterial blood samples or any blood samples collected early after injection of the radiotracer.